Signatures of Mutational Processes in Human Cancer

Somatic mutations are present in all cells of the human body and occur throughout life. They are the consequence of multiple mutational processes, including the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, enzymatic modification of DNA and defective DNA repair. Different mutational processes generate unique combinations of mutation types, termed “Mutational Signatures”.

The current set of mutational signatures is based on an analysis of 10,952 exomes and 1,048 whole-genomes across 40 distinct types of human cancer. These analyses are based on curated data that were generated by The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and a large set of freely available somatic mutations published in peer-reviewed journals. Complete details about the data sources will be provided in future releases of COSMIC.

The profile of each signature is displayed using the six substitution subtypes: C>A, C>G, C>T, T>A, T>C, and T>G (all substitutions are referred to by the pyrimidine of the mutated Watson–Crick base pair). Further, each of the substitutions is examined by incorporating information on the bases immediately 5’ and 3’ to each mutated base generating 96 possible mutation types (6 types of substitution ∗ 4 types of 5’ base ∗ 4 types of 3’ base). Mutational signatures are displayed and reported based on the observed trinucleotide frequency of the human genome, i.e., representing the relative proportions of mutations generated by each signature based on the actual trinucleotide frequencies of the reference human genome version GRCh37. Note that only validated mutational signatures have been included in the curated census of mutational signatures.

Additional information is provided for each signature, including the cancer types in which the signature has been found, proposed aetiology for the mutational processes underlying the signature, other mutational features that are associated with each signature and information that may be relevant for better understanding of a particular mutational signature.

The set of signatures will be updated in the future. This will include incorporating additional mutation types (e.g., indels, structural rearrangements, and localized hypermutation such as kataegis) and cancer samples. With more cancer genome sequences and the additional statistical power this will bring, new signatures may be found, the profiles of current signatures may be further refined, signatures may split into component signatures and signatures may be found in cancer types in which they are currently not detected.

All the data used for deriving the 30 mutational signatures in COSMIC are publicly and freely available. Please note that most of these data were generated as part of studies performed by others. Information about the data sources containing these freely available data is provided in Supplementary Data 1 of “Clock-like mutational processes in human somatic cells” Nature Genetics, 2015, 47, 1402-1407. This information can be used to download any sample from its respective data source.

Signature 1

Cancer types:

Signature 1 has been found in all cancer types and in most cancer samples.

Proposed aetiology:

Signature 1 is the result of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine.

Additional mutational features:

Signature 1 is associated with small numbers of small insertions and deletions in most tissue types.

Comments:

The number of Signature 1 mutations correlates with age of cancer diagnosis.

Signature 2

Signature 2

Cancer types:

Signature 2 has been found in 22 cancer types, but most commonly in cervical and bladder cancers. In most of these 22 cancer types, Signature 2 is present in at least 10% of samples.

Proposed aetiology:

Signature 2 has been attributed to activity of the AID/APOBEC family of cytidine deaminases. On the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems, a role for APOBEC1, APOBEC3A and/or APOBEC3B in human cancer appears more likely than for other members of the family.

Additional mutational features:

Transcriptional strand bias of mutations has been observed in exons, but is not present or is weaker in introns.

Comments:

Signature 2 is usually found in the same samples as Signature 13. It has been proposed that activation of AID/APOBEC cytidine deaminases is due to viral infection, retrotransposon jumping or to tissue inflammation. Currently, there is limited evidence to support these hypotheses. A germline deletion polymorphism involving APOBEC3A and APOBEC3B is associated with the presence of large numbers of Signature 2 and 13 mutations and with predisposition to breast cancer. Mutations of similar patterns to Signatures 2 and 13 are commonly found in the phenomenon of local hypermutation present in some cancers, known as kataegis, potentially implicating AID/APOBEC enzymes in this process as well.

Signature 3

Signature 3

Cancer types:

Signature 3 has been found in breast, ovarian, and pancreatic cancers.

Proposed aetiology:

Signature 3 is associated with failure of DNA double-strand break-repair by homologous recombination.

Additional mutational features:

Signature 3 associates strongly with elevated numbers of large (longer than 3bp) insertions and deletions with overlapping microhomology at breakpoint junctions.

Signature 4

Cancer types:

Signature 4 has been found in head and neck cancer, liver cancer, lung adenocarcinoma, lung squamous carcinoma, small cell lung carcinoma, and oesophageal cancer.

Proposed aetiology:

Signature 4 is associated with smoking and its profile is similar to the mutational pattern observed in experimental systems exposed to tobacco carcinogens (e.g., benzo[a]pyrene). Signature 4 is likely due to tobacco mutagens.

Additional mutational features:

Signature 4 exhibits transcriptional strand bias for C>A mutations, compatible with the notion that damage to guanine is repaired by transcription-coupled nucleotide excision repair. Signature 4 is also associated with CC>AA dinucleotide substitutions.

Comments:

Signature 29 is found in cancers associated with tobacco chewing and appears different from Signature 4.

Signature 5

Signature 5

Cancer types:

Signature 5 has been found in all cancer types and most cancer samples.

Additional mutational features:

Comments:

Signature 6

Cancer types:

Signature 6 has been found in 17 cancer types and is most common in colorectal and uterine cancers. In most other cancer types, Signature 6 is found in less than 3% of examined samples.

Proposed aetiology:

Signature 6 is associated with defective DNA mismatch repair and is found in microsatellite unstable tumours.

Additional mutational features:

Signature 6 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 6 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 15, 20, and 26.

Signature 7

Signature 7

Cancer types:

Signature 7 has been found predominantly in skin cancers and in cancers of the lip categorized as head and neck or oral squamous cancers.

Proposed aetiology:

Based on its prevalence in ultraviolet exposed areas and the similarity of the mutational pattern to that observed in experimental systems exposed to ultraviolet light Signature 7 is likely due to ultraviolet light exposure.

Additional mutational features:

Signature 7 is associated with large numbers of CC>TT dinucleotide mutations at dipyrimidines. Additionally, Signature 7 exhibits a strong transcriptional strand-bias indicating that mutations occur at pyrimidines (viz., by formation of pyrimidine-pyrimidine photodimers) and these mutations are being repaired by transcription-coupled nucleotide excision repair.

Additional mutational features:

Comments:

Signature 9

Cancer types:

Signature 9 has been found in chronic lymphocytic leukaemias and malignant B-cell lymphomas.

Proposed aetiology:

Signature 9 is characterized by a pattern of mutations that has been attributed to polymerase η, which is implicated with the activity of AID during somatic hypermutation.

Additional mutational features:

N/A

Comments:

Chronic lymphocytic leukaemias that possess immunoglobulin gene hypermutation (IGHV-mutated) have elevated numbers of mutations attributed to Signature 9 compared to those that do not have immunoglobulin gene hypermutation.

Signature 10

Signature 10

Cancer types:

Signature 10 has been found in six cancer types, notably colorectal and uterine cancer, usually generating huge numbers of mutations in small subsets of samples.

Proposed aetiology:

It has been proposed that the mutational process underlying this signature is altered activity of the error-prone polymerase POLE. The presence of large numbers of Signature 10 mutations is associated with recurrent POLE somatic mutations, viz., Pro286Arg and Val411Leu.

Additional mutational features:

Comments:

Signature 10 is associated with some of most mutated cancer samples. Samples exhibiting this mutational signature have been termed ultra-hypermutators.

Signature 11

Signature 11

Cancer types:

Signature 11 has been found in melanoma and glioblastoma.

Proposed aetiology:

Signature 11 exhibits a mutational pattern resembling that of alkylating agents. Patient histories have revealed an association between treatments with the alkylating agent temozolomide and Signature 11 mutations.

Additional mutational features:

Signature 11 exhibits a strong transcriptional strand-bias for C>T substitutions indicating that mutations occur on guanine and that these mutations are effectively repaired by transcription-coupled nucleotide excision repair.

Proposed aetiology:

Additional mutational features:

Comments:

Signature 12 usually contributes a small percentage (<20%) of the mutations observed in a liver cancer sample.

Signature 13

Signature 13

Cancer types:

Signature 13 has been found in 22 cancer types and seems to be commonest in cervical and bladder cancers. In most of these 22 cancer types, Signature 13 is present in at least 10% of samples.

Proposed aetiology:

Signature 13 has been attributed to activity of the AID/APOBEC family of cytidine deaminases converting cytosine to uracil. On the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems, a role for APOBEC1, APOBEC3A and/or APOBEC3B in human cancer appears more likely than for other members of the family. Signature 13 causes predominantly C>G mutations. This may be due to generation of abasic sites after removal of uracil by base excision repair and replication over these abasic sites by REV1.

Additional mutational features:

Transcriptional strand bias of mutations has been observed in exons, but is not present or is weaker in introns.

Comments:

Signature 2 is usually found in the same samples as Signature 13. It has been proposed that activation of AID/APOBEC cytidine deaminases is due to viral infection, retrotransposon jumping or to tissue inflammation. Currently, there is limited evidence to support these hypotheses. A germline deletion polymorphism involving APOBEC3A and APOBEC3B is associated with the presence of large numbers of Signature 2 and 13 mutations and with predisposition to breast cancer. Mutations of similar patterns to Signatures 2 and 13 are commonly found in the phenomenon of local hypermutation present in some cancers, known as kataegis, potentially implicating AID/APOBEC enzymes in this process as well.

Signature 14

Signature 14

Cancer types:

Signature 14 has been observed in four uterine cancers and a single adult low-grade glioma sample.

Proposed aetiology:

The aetiology of Signature 14 remains unknown.

Additional mutational features:

N/A

Comments:

Signature 14 generates very high numbers of somatic mutations (>200 mutations per MB) in all samples in which it has been observed.

Signature 15

Signature 15

Cancer types:

Signature 15 has been found in several stomach cancers and a single small cell lung carcinoma.

Proposed aetiology:

Signature 15 is associated with defective DNA mismatch repair.

Additional mutational features:

Signature 15 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 15 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 20, and 26.

Proposed aetiology:

Additional mutational features:

Comments:

Signature 18

Cancer types:

Signature 18 has been found commonly in neuroblastoma. Additionally, Signature 18 has been also observed in breast and stomach carcinomas.

Proposed aetiology:

The aetiology of Signature 18 remains unknown.

Additional mutational features:

N/A

Comments:

N/A

Signature 19

Signature 19

Cancer types:

Signature 19 has been found only in pilocytic astrocytoma.

Proposed aetiology:

The aetiology of Signature 19 remains unknown.

Additional mutational features:

N/A

Comments:

N/A

Signature 20

Signature 20

Cancer types:

Signature 20 has been found in stomach and breast cancers.

Proposed aetiology:

Signature 20 is believed to be associated with defective DNA mismatch repair.

Additional mutational features:

Signature 20 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 20 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 15, and 26.

Signature 21

Signature 21

Cancer types:

Signature 21 has been found only in stomach cancer.

Proposed aetiology:

The aetiology of Signature 21 remains unknown.

Additional mutational features:

N/A

Comments:

Signature 21 is found only in four samples all generated by the same sequencing centre. The mutational pattern of Signature 21 is somewhat similar to the one of Signature 26. Additionally, Signature 21 is found only in samples that also have Signatures 15 and 20. As such, Signature 21 is probably also related to microsatellite unstable tumours.

Signature 22

Signature 22

Cancer types:

Signature 22 has been found in urothelial (renal pelvis) carcinoma and liver cancers.

Proposed aetiology:

Signature 22 has been found in cancer samples with known exposures to aristolochic acid. Additionally, the pattern of mutations exhibited by the signature is consistent with the one previous observed in experimental systems exposed to aristolochic acid.

Proposed aetiology:

Additional mutational features:

Comments:

N/A

Signature 24

Signature 24

Cancer types:

Signature 24 has been observed in a subset of liver cancers.

Proposed aetiology:

Signature 24 has been found in cancer samples with known exposures to aflatoxin. Additionally, the pattern of mutations exhibited by the signature is consistent with that previous observed in experimental systems exposed to aflatoxin.

Proposed aetiology:

Additional mutational features:

Comments:

This signature has only been identified in Hodgkin’s cell lines. Data is not available from primary Hodgkin lymphomas.

Signature 26

Signature 26

Cancer types:

Signature 26 has been found in breast cancer, cervical cancer, stomach cancer and uterine carcinoma.

Proposed aetiology:

Signature 26 is believed to be associated with defective DNA mismatch repair.

Additional mutational features:

Signature 26 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 26 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 15 and 20.

Signature 27

Signature 27

Cancer types:

Signature 27 has been observed in a subset of kidney clear cell carcinomas.

Proposed aetiology:

The aetiology of Signature 27 remains unknown.

Additional mutational features:

Signature 27 exhibits very strong transcriptional strand bias for T>A mutations. Signature 27 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

N/A

Signature 28

Signature 28

Cancer types:

Signature 28 has been observed in a subset of stomach cancers.

Proposed aetiology:

The aetiology of Signature 28 remains unknown.

Additional mutational features:

N/A

Comments:

N/A

Signature 29

Signature 29

Cancer types:

Signature 29 has been observed only in gingivo-buccal oral squamous cell carcinoma.

Proposed aetiology:

Signature 29 has been found in cancer samples from individuals with a tobacco chewing habit.